generation-on-demand-initiation-acute-ictal-activity-rodent-human

Generation and On-Demand Initiation of Acute Ictal Activity in Rodent and Human Tissue

Controlling seizures remains a challenging issue for the medical community. To make progress, researchers need a way to extensively study seizure dynamics ...

KREMBIL RESEARCH INSTITUTE

University of Toronto

Extracellular potassium concentration, [K⁺], plays a fundamental role in the physiological functions of the brain. Studies investigating changes in [K⁺] have predominantly relied upon glass capillary electrodes with K⁺-sensitive solution gradients for their measurements. However, such electrodes are unsuitable for taking spatio-temporal measurements and are limited by the surface area of their tips. We illustrate seizures invoked chemically and in optogenetically modified mice using blue light exposure while impedimetrically measuring the response. A sharp decrease of 1-2 mM in [K⁺] before each spike has shown new physiological events not witnessed previously when measuring extracellular potassium concentrations during seizures in mice. We propose a novel approach that uses multichannel monolayer coated gold microelectrodes for in vivo spatio-temporal measurements of [K⁺] in a mouse brain as an improvement to the conventional glass capillary electrode.

Biofouling-Resistant Impedimetric Sensor for Array High-Resolution Extracellular Potassium Monitoring in the Brain.

Activation of γ-aminobutyric acid (GABA) receptors have been associated with the onset of epileptiform events. To investigate if a causal relationship exists between GABA receptor activation and ictal event onset, we activated inhibitory GABAergic networks in the superficial layer (2/3) of the somatosensory cortex during hyperexcitable conditions using optogenetic techniques in mice expressing channelrhodopsin-2 in all GABAergic interneurons. We found that a brief 30ms light pulse reliably triggered either an interictal-like event (IIE) or ictal-like ("ictal") event in the in vitro cortical 4-Aminopyridine (4-AP) slice model. The link between light pulse and epileptiform event onset was lost following blockade of GABA receptors with bicuculline methiodide. Additionally, recording the chronological sequence of events following a light pulse in a variety of configurations (whole-cell, gramicidin-perforated patch, and multi-electrode array) demonstrated an initial hyperpolarization followed by post-inhibitory rebound spiking and a subsequent slow depolarization at the transition to epileptiform activity. Furthermore, the light-triggered ictal events were independent of the duration or intensity of the initiating light pulse, suggesting an underlying regenerative mechanism. Moreover, we demonstrated that brief GABA receptor activation can initiate ictal events in the in vivo 4-AP mouse model, in another common in vitro model of epileptiform activity, and in neocortical tissue resected from epilepsy patients. Our findings reveal that the synchronous activation of GABAergic interneurons is a robust trigger for ictal event onset in hyperexcitable cortical networks.

Suzie Dufour

Division of Fundamental Neurobiology

KREMBIL RESEARCH INSTITUTE

Generation and On-Demand Initiation of Acute Ictal Activity in Rodent and Human Tissue

Suzie Dufour

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KREMBIL RESEARCH INSTITUTE

Generation and On-Demand Initiation of Acute Ictal Activity in Rodent and Human Tissue

Division of Fundamental Neurobiology